Departments of Internal Medicine (Section of Medical Oncology) and Pharmacology, and the Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, Room WWW217, New Haven, CT 06510, USA.
Breast Cancer Res Treat. 2010 Apr;120(2):327-35. doi: 10.1007/s10549-009-0382-5. Epub 2009 Apr 1.
The insulin-like growth factor I receptor (IGF1R) interacts with estrogen receptor-alpha (ERalpha) and HER2. We examined the effect of combinations of IGF1R antagonists (alpha-IR3, AG1024) and anti-estrogens (4-hydroxy tamoxifen, fulvestrant) in two human ER+ breast cancer cell lines: BT474 (HER2 overexpressing, IGF1R low) and MCF7 (HER2 non-overexpressing, IGF1R high). In BT474 cells, growth was inhibited by anti-estrogens, but not by IGF1R antagonists; however, adding IGF1R inhibitors to anti-estrogens enhanced growth inhibition. In MCF7 cells, growth was inhibited by IGF1R and ER antagonists and more so by their combination. In both cell lines, no single agents could induce apoptosis, but combining IGF1R inhibitors with anti-estrogens induced dramatic levels of apoptosis. IGF1R antagonists enhanced the ability of the anti-estrogens to inhibit ER transcriptional activity in BT474 cells, but not in MCF7 cells. The drug combination synergistically inhibited ER and IGF1R activity. Such combinations may be useful therapy for breast cancer.
胰岛素样生长因子 I 受体（IGF1R）与雌激素受体-α（ERα）和 HER2 相互作用。我们研究了 IGF1R 拮抗剂（alpha-IR3、AG1024）和抗雌激素（4-羟基他莫昔芬、氟维司群）联合应用对两种人 ER+乳腺癌细胞系（BT474[HER2 过表达，IGF1R 低]和 MCF7[HER2 非过表达，IGF1R 高]）的影响。在 BT474 细胞中，生长被抗雌激素抑制，但不受 IGF1R 拮抗剂的影响；然而，将 IGF1R 抑制剂加入抗雌激素中增强了生长抑制作用。在 MCF7 细胞中，IGF1R 和 ER 拮抗剂以及它们的组合抑制了生长。在这两种细胞系中，没有单一药物能够诱导细胞凋亡，但将 IGF1R 抑制剂与抗雌激素联合使用可诱导显著水平的细胞凋亡。IGF1R 拮抗剂增强了抗雌激素抑制 BT474 细胞中 ER 转录活性的能力，但在 MCF7 细胞中没有。药物组合协同抑制 ER 和 IGF1R 活性。这种联合用药可能对乳腺癌的治疗有用。
